Clinical Genetics
Pediatric Residents
Deborah Lyn, Ph.D
Email: dlyn@msm.edu
Phone: 404-752-1521
November 2009
Family History is the First Step in
Constructing a Pedigree
Questions to consider:
• Is the transmitted disease due to the inheritance
(predisposition) of a cancer-related gene or chromosomal
abnormality?
• Does the pattern of transmission follow Mendelian mode of
inheritance?
Parent does not manifest cancer, but risk is passed to next
generation.
Single Gene Inheritance:
(Monogenic)
Nuclear Genome
• Assumes a single gene defect.
• Allelic frequency usually <0.1%.
• Transmitted on autosomal, X or Y chromosome
(follow Mendelian pedigree pattern).
• Disease likely to be severe, occur at early age of
onset.
• Severity may depend on location of gene defect.
• Complicated by environmental modifiers.
Dominant inheritance: heterozygotes display phenotype
Recessive inheritance: homozygotes display phenotype
http://genetics.gsk.com
Autosomal dominant diseases:
Huntington’s, Myotonic Dystrophy, Marfan syndrome
Inheritance of an Autosomal Dominant
Disorder
• Male to male transmission observed.
• Ratios of affected offspring will give clues to mode of inheritance.
• Heterozygotes will display the disease.
recessive
http://genetics.gsk.com
Recessive traits:
Sickle cell anemia
Cystic fibrosis
Phenylketonuria- mutation in phenylalanine hydroxylase.
Autosomal Recessive
(a) What is the probability of aa from Aa heterozygote parents?
(b) All offspring will be Aa.
X-Linked Disorders
• X-linked disorders are notable for their
expression in males.
• Males always display disease when they inherit
mutant gene.
• X-linked dominant and recessive genes are
only applicable in females.
• Absence of father to son transmission, but
daughters of a male with an X-linked trait must
inherit the mutant gene.
X-Linked Recessive Inheritance
http://ordc.ohsu.edu/disease-information/inheritance
Family with X-linked choroideremia, due to a mutation in
the gene CHM, which is located on the X chromosome. The
asterisk represents a mutation within that gene.
http://genetics.gsk.com
Menke’s disease [defect in copper transport]
Hemolytic anemia (mutation in glucose 6-phosphate dehydrogenase).
Punnett Square for
X-Linked Recessive
Inheritance
Normal
MotherХs
Genotype
Affected FatherХs
Genotype
XA
Y
X
XXA
XY
A
X
XX
XY
Inheritance of an X-linked Dominant
Disorder
X-Chromosome Inactivation
[implantation of embryo]
Fig. 7.4 ©Scion Publishing Ltd
Complication to X-Linked Inheritance
X-Chromosome Inactivation
Lyon Hypothesis
•
•
•
•
One X chromosome in each cell is randomly inactivated in the
embryonic development of females. (Paternal and maternal
derived x chromosome will be inactivation in about half of the
embryos’ cells).
Compensate for gene dosage on X-chromosome between males
and females.
Inactivation is permanent once it is determined.
In females, X chromosome exhibits somatic cell mosaics.
Barr Body in females is due to a condensed heterochromatin
structure (transcriptional inactive).
• X-chromosome inactivation will affect disease severity, and
complicate pattern of recessive inheritance.
Turner’s Syndrome
• Monosomy X chromosome: Xm (maternal) or
Xp (paternal).
• Barr body is not detectable.
• No X-inactivation.
• Intelligence usually normal, but impaired
social competence and adjustment.
Other Factors That Complicate
Mendelian Patterns
New Mutation
• A child will be born with a disease for which there is no
previous history of the disease in the family.
New autosomal dominant mutation, appears to mimic an
autosomal or X-linked recessive pattern.
New Mutation
•
•
•
•
Chromosomal abnormality (meiosis).
Post-zygotic event (mitosis).
New dominant mutation (altered protein structure).
Sporadic change-tumor development - environmental
exposure.
• Exposure to viral infection.
– Congenital rubella syndrome.
• Exposure to teratogenic agent during pregnancy.
– Fetal alcohol syndrome.
– Neural tube defect.
– Cigarette smoking (embryonic hypoxia).
Exposure Within First Trimester Can Result in
Craniofacial Malformations
J Orofac Orthop (2007) 68: 266-277
Vitamin B6, B12 and folic acid:
Role in One-carbon Transfer Reactions.
• Purine, pyrimidine synthesis.
• Cytosine methylation.
• Methylation of histones.
Germline Mosaicism
Centre for Genetics Education. Http://www.genetics.edu.au
Variable Expression
• Severity of the disease can vary greatly - modified
by environment, modifier genes (protein variants).
• Heteroplasmic mitochondrial mutation.
• Mosaicism (e.g. Due to X-chromosome
inactivation).
Uniparental Disomy (UPD)
Inheritance of both autosomal chromosomes
(or a segment) from the same parent.
Impact observed in:
• Genes regulated by genomic imprinting.
• Mitochondrial inheritance.
• Skew pattern of recessive inheritance.
Uniparental Disomy (UPD)
r r
N N
X
r r
N N
X
r N
r r
Heterozygote:
No display of
phenotype/disease
Autosomal Recessive
Trisomy rescue
Homozygosity arises as a result
of UPD
Loss of Mendelian Principles->
even segregation and
independent assortment of
chromosomes.
Single Gene Inheritance
Mitochondrial Genome
• Assumes a single gene defect.
• Severity may depends on percentage of
mitochondria bearing mutation (homoplasmy
versus heteroplasmy).
• Genome more vulnerable to mutations: higher
incidence of acquired diseases associated with
aging.
• Diseases of cardiac and skeletal muscle are
common-mitochondrial myopathies.
• Diseases of nervous system.
• Egg contributes most of the mitochondria to the
zygote.
Egg Contributes
Most of the
Mitochondria to
the Zygote
Inheritance of Variable Severity
Oogenesis
“Heteroplasmy” more than one population of mitochondrial DNA
in the cell.
Individuals harbor multiple copies of mitochondrial
genome.
Characteristics of
Mitochondrial Inheritance
• Mitochondrial disorders are inherited maternally. Both
male and female offspring are affected, but affected
males cannot transmit the disease.
• Mutations in genes involved with oxidative
phosphorylation.
– Leber’s hereditary optic neuropathy (mutation in electron
transport protein NADH-coenzyme Q).
– Myoclonus Epilepsy Associated with Ragged-Red Fibers
(MERRF)
– Mitochondrial Encephalomyopathy with Lactic Acidosis and
Stroke-like Episodes (MELAS).
• Homoplasmy and heteroplasmy mutations.
Pedigree Showing Transmission and
Expression of a Mitochondrial Trait
[probably due to heteroplasmy]
Note that transmission occurs only through females (circles).
Multi-factorial Inheritance
“One Gene One Phenotype” hypothesis
is not applicable.
Spectrum of human characters: from “Human Molecular Genetics by Strachan & Read.
The Threshold Model for Multi-factorial Traits
healthy
disease
Figure 15: Below the threshold, the trait
is not expressed. Individuals above the
threshold have the disease.
[Figures from: www.uic.edu/classes/bms/bms655/gfx]
Figure 18: Recurrence risk to first degree
relatives of affected individuals.
-Body mass index
-Height
-Blood pressure
-Phenotype is present or absent.
-Cleft lip, cleft palate.
Phenotype is Combination of
Genotypes + Epigenome +
Environment
Deviations From Expected Ratios
May Be Due To:
• Alleles show incomplete dominance or co-dominance.
• Genes under investigation are closely linked on the same
chromosome.
• X-linked inactivation may result in manifesting
heterozygote females.
• Genetic interactions between different genes.
• Trait is inherited on genetic material from only one
parent. e.g. mitochondrial DNA is only inherited from the
mother.
• Gene is imprinted.
Genetic Variation is More than a SNP
Chromosomal Defects
DiGeorge Syndrome
• Deletion at chromosome 22q11. Variation in symptoms is
related to the amount of genetic material lost.
• CHARGE association (coloboma, heart defect, choanal
atresia, growth or developmental retardation, genital
hypoplasia, and ear anomalies, including deafness).
• Cardiac and some speech impairments may be corrected
surgically or therapeutically.
• DGS gene is required for the normal development of the
thymus (reduced T-cell function) and parathyroid gland.
• “Complete DiGeorge anomaly" is used to describe infants
who are athymic. Those with “typical” phenotype have
low T-cell numbers.
• Some success with thymus transplantation.
Spontaneous Fetal Loss for
Autosomal Trisomies
Fig 3.1, Medical Genetics (1999) G.H. Sack, Jr. McGraw-Hill.
Poor survival of trisomy 13 (Patau syndrome) and 18 (Edwards syndrome)
conception, but no survival of trisomy 16.
Maternal Age is Associated with Rise
in Incidence in Trisomy
http://www.bio.miami.edu/~cmallery/150/mendel/heredity.htm
Robertsonian Translocation
Non-Homologous Rearrangement
Long arms of acrocentric chromosome fuse at centromere, short
arms are lost.
Down Syndrome due to Robertsonian
Translocation
Translocation trisomy
Robertsonian translocation arises from fusion of long arms of
chromosome 21 and 14 [46 t(14;21)].
Translocation Down syndrome
• Accounts for 5% of cases.
• Woman with balanced translocation have high
recurrent risk of producing a second child with
Down syndrome.
• ROBs usually occur during meiosis and originate
from a single parent.
• Post-zygotic model would predict random
translocation events.
Patau Syndrome
• Trisomy 13; 1/12,000 births.
• Short life-span, mean survival is 95 days. Longer
survival linked with heteromorphisms.
• Clinical triad (microphthalmia/eye development
disorder, cleft lip/palate, and polydactyly). Other
facial deformities - abnormally small ears, small jar.
• Non-cyanotic heart defects.
• Intra-uterine growth retardation, single umbilical
artery (evident on sonogram).
• Associated with advanced age of parents.
Patau Syndrome - Trisomy 13
Cytogenetic mosaicism - longer survival, variable expression.
European Journal of Medical Genetics (2008) 51, July-August
Fig. 1. Phenotypic aspects of the patient. The infant at birth (A) and at 12 years (B); pigmentary
mosaicism on the back (C); feet (D). Linear white streaks are evident on both feet.
Contiguous Gene Syndromes
• Involves micro-deletions spanning multiple,
adjacent genes positioned along a chromosome.
• Require FISH (fluorescent in situ hybridization) for
detection.
• Imprinted genes usually located in cluster and
harbor long range cis-acting DNA elements
(imprint control element).
• Outcome of a contiguous deletion of imprinted
genes is dependent on the chromosomal parent of
origin.
Normal Embryos Can ONLY Arise When
Maternal and Paternal Genomes Are
Combined
www.mcb.ucdavis.edu/.../chedin/research.htm
Modified from Janine LaSalle
Expression of Imprinted Genes
• Haploid genome is not equivalent in regards to gene
transcription.
• Selective Expression/Transcription from either
maternal or paternal allele.
• Selective gene silencing from either maternal or
paternal allele. Does not occur on every
chromosome.
• Occurs during gametogenesis.
• Disease manifestation is dependent on allelic loss of
normally transcribed gene.
• Usually involved with development and post-natal
growth.
Beckwith-Wiedemann Syndrome
(overgrowth disorder)
CH3
Maternal
IGF2
H19
CH3
Paternal
IGF2
H19
transcription
Normal Function Depends on Coordinated IGF2 (insulin-like growth factor2) and H19 (non-coding RNA) genes expression on chromosome
11p15.5.
IGF2 gene is normally silenced on maternal chromosome.
In BWS, biallelic expression of IGF2 gene; escape of epigenetic silencing.
Silver Russell Syndrome
Maternal
CH3
IGF2
Paternal
H19
Chromosome 11p15
CH3
IGF2
H19
transcription
Epimutation is opposite to BWS.
Biallelelic expression of H19 genes on both parental
chromosomes, due to loss of methylation at imprint control
region of H19.
Reduced expression of IGF2.
SRS-like condition is also due to loss imprint control on
chromosome 7p.
Silver Russell Syndrome
Poor intrauterine growth: low birth weight, small for
gestational age.
Cranofacial features, triangular shaped face
(pointed small chin), broad forehead.
Body asymmetry of arms and legs.
Fifth finger clinodactyly.
Normal mental development.
Expression of
Paternal “A” Gene is
Lost.
Monoallelic Expression of Genes at 15q11-13
Deletion of paternally expressed genes -> Prader Willi syndrome.
Deletion of maternally expressed genes -> Angelman syndrome
Fig. 7.18 ©Scion Publishing Ltd
Prader-Willi and Angelman syndrome
Neurogenetic Disorders Caused by the Lack of a
Paternal or a Maternal Contribution from
Chromosome 15q11-q13.
Fig 3.13, Medical Genetics (1999) G.H. Sack, Jr. McGraw-Hill.
Prader-Willi
Angelman
15q11-13
Genomic Imprint of PWS and AS Gene Clusters:
Monoallelic Expression at Chromosome 15q
Selective expression of genes from this chromosome
Transcriptional silencing
UDP: Uniparental Disomy
IC: Imprint Control region
ID: Imprint Deletion/Mutation in Regulatory Sequences
Prader-Willi Syndrome
• 1 in 10,000-1,25,000.
• Fetal phenotype: fetal movement is diminished, amniotic
fluid in lower range, abnormal fetal position, low birth
weight.
• At birth: hypotonic with difficult feeding, facial
dysmorphism; difficulty establishing respiration.
• Hypogonadism, may have undescended testes in males.
• Misdiagnosed as Down syndrome, due to marked obesity.
• Genetic test can distinguish chromosome difference,
Methylation sensitive PCR, polymorphic markers can
separate UPD.
Prader-Willi Syndrome
• Childhood: Excessive sleeping, failure to thrive, delayed
milestones, speech delay.
• Hyperphagia/ change in feeding from infancy.
• Learning disability, but some cases of average intelligence.
• Early intervention requires GH injections to support increased
muscle mass and reduce food re-occupation.
• Adolescence: Delayed puberty (girls have premature
adrenarche), short stature, obesity, excessive eating.
• Adult: Uncertain fertility outcome especially in boys. Prone to
diabetes.
• General: small hands and feet, high narrow forehead, excess
fat, light skin and hair relative to other family members.
Angelman Syndrome
• Severe mental retardation.
• Delayed motor development, absence of speech, lack of
balance, jerky movements (“puppet”).
• Excessive laughter.
• Typical face: wide spread teeth, broad mouth, protruding
tongue, and prominent chin.
• Caused by loss of function of the imprinted UBE3A (ubiquitin
ligase3A) gene.
Summary
del 15(q11-q13)
del 15(q11-q13)
Prader-Willi Syndrome
AngelMan Syndrome
70% Paternal Deletion
25% Maternal Uniparental Disomy
5% Imprinting Defect
70%
4%
3-5%
1%
10%
Maternal Deletion
Paternal Uniparental Disomy
Sequence mutation in UBE3A gene
Chromosomal rearrangement
Unknown
Website from Univ. Florida
http://www.peds.ufl.edu/divisions/genetics/teaching-resources.htm