Chapter 41

Genetic Disorders

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 Introduction
 Evolving understanding of human genome
transforming understanding of genetics,
embryology, physiology, disease processes
 Genome-based science expanded beyond study
of single genes to
 Interaction of genes across genome
 How interactions are influenced by environment,
random events, epigenetic factors
 All diseases/responses to disease have
genetic/genomic components
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BASIC PRINCIPLES OF GENETICS

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 DNA
 One egg/one sperm establish unique DNA package for each human
 Total DNA package – genome
 Genetic information flows from DNA to RNA to protein – each gene
codes for up to 20 proteins
 DNA composed of string of nucleotides – each nucleotide consists
of
 Deoxyribose
 Phosphate group
 One of 4 bases: adenine (A), cytosine (C), guanine (G), and thymine
(T)
 “Backbones” of DNA helix formed by deoxyribose and phosphate
groups
 “Rungs” formed by complementary pairing (A-T and C-G) of the
bases
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 DNA
 Differences between humans form only 0.1% of
DNA
 Even a slight alteration in DNA can have
devastating consequences
 Sickle cell anemia caused by an alteration of a single
nucleotide
 Some alterations have no known effects; others
provide benefits or protective actions

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 Chromosomes
 Cytogenetics – study of genetics at chromosome
level
 Each chromosome has a strand of DNA
 Nucleus of all human cells except gametes
contain 46 chromosomes in 23 pairs
 22 are autosomes; are same in males/females
 Sex chromosomes differ between males/females
 Karyotype – picture of chromosomes lined up in
pairs

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 Chromosomes
 Human somatic cells are diploid, with 23 paired
chromosomes
 Replicate by mitosis – creating two identical daughter
cells
 Gametes are haploid, with 23 chromosomes
 Produced in ovary or testicle during meiosis
 Exchange of genetic material – random assortment of
maternally/paternally derived genetic material in
daughter cells
 Fusion at fertilization restores the 46-chromosome
complement
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 Chromosomes
 Chromosomes – long arm (q) and short arm (p)
 Ideogram used to show size and banding pattern
 Bands further describe location of genes on chromosomes
 Cytogenic location of CFTR gene for CF is 7q31.2, meaning a location
on long arm of chromosome 7, band 3, sub-band 1, and sub-sub-band 2
 Telomeres are protective caps at ends of each chromosome
 Contain and protect genetic information on chromosome
 Shorten each time a cell divides; lose protective function over time
 Stress can affect telomeres – increased risks for adult health problems
may be related to stress and shortening of telomeres

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 Genes
 Specific coding sequence of DNA organized in small blocks of three
letters (codon)
 64 different codons in genetic code
 One gene codes for average of three proteins
 Genotype – individual’s collection of genes
 Phenotype – manifestation of genotype
 Gene expression regulated by molecular mechanisms/modified by
environmental factors
 Two copies of each gene inherited; one copy (allele) from each
parent
 Homozygous – two alleles similar
 Heterozygous – two alleles different

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 Genes
 Genes vary from 200 to more than 2 million DNA bases
 Humans may have 20,000 to 25,000 genes
 Every cell contains every gene; not all are active at once
 Mechanisms activate genes to turn on and off
 Exons – coding sequences
 Introns – non-coding sequences
 Occupy specific locations on chromosomes
 Small number of genes in mitochondria

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 Mutations
 Mutation – variation in <1% of population
 Often disease-causing
 Polymorphism – in >1% of population
 Usually considered normal variation
 Single-nucleotide polymorphism (SNP) – single-
based pair alteration common in a given
population
 Not directly disease-causing, but help identify those at
risk for multifactorial disease or adverse response to
medications

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 Mutations
 Point mutations – single base pair changes
 Responsible for many single-gene disorders
 Nucleotide repeat expansions – occur beyond single
point changes
 When number of repeats high enough, a genetic disorder results
 Copy number variations – involves larger areas of
chromosomes; may lose or gain copies of genetic
information present in parents
 Common psycho-behavioral diseases
 Chromosome mutations – involve larger segments
 Multi-organ, large effects, as in Down syndrome

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TYPES OF GENETIC DISORDERS

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 Monogenetic Disorders
 Occur when mutation affects single gene
 Dominant – mutation on one allele
 Recessive – mutation on both alleles
 X-linked – confined to X chromosome

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 Chromosome Disorders
 Changes in number/structure of entire
chromosome
 Prader-Willi – absence of group of genes
 Down syndrome – extra copy of chromosome
 Mosaicism – altered chromosomal arrangement
in some cells but not others
 Milder symptoms with better prognosis

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 Multifactorial Disorders
 Combination of genetic/environmental factors
 Spina bifida
 Tend to cluster in families
 Population-based recurrence risk is calculated,
rather than personal recurrence risk

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 Teratogens
 Any agent resulting in or increasing incidence of
congenital malformation
 Genomic factors can significantly modify effects
of teratogen

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 Mitochondrial Disorders
 Mitochondrial DNA contains 37 genes
 Exclusively maternal transmission

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PATTERNS OF INHERITANCE

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Patterns of Inheritance

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 Patterns of Inheritance
 Mendelian inheritance patterns
 Autosomal dominant
 Autosomal recessive
 X-linked dominant
 X-linked recessive

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 Autosomal Dominant
 Inheritance of single copy of mutated gene
 Passed on from only one parent, but results in
genetic disorder because gene is dominant
 Donating parent has disorder
 Risk for inheriting is 50% for each child

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 Autosomal Recessive
 Requires inheritance of two copies of mutated
gene; one from each parent
 Offspring with only one copy are carriers
 Carriers may pass genes to children, but are
themselves unaffected
 Risk for inheriting is 25% for each child, 50% risk
for being a carrier; 25% risk of being unaffected

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 X-Linked Dominant
 Single abnormal gene on X chromosome causes
disease
 If father affected and mother not, all female
offspring will inherit disease
 If mother affected and father not, 50% chance
that each daughter/son will inherit

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 X-Linked Recessive
 Usually occurs in males who have only one X
chromosome

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 Non-Traditional Inheritance Patterns
 Mitochondrial inheritance
 Passed on by mothers
 Co-dominant inheritance
 Two alleles for gene expressed
 Genetic imprinting
 Occurs during embryogenesis – one gene copy activated; other
inactivated
 Improper imprinting can result in two active or inactive copies of
genes
 Uniparental disomy
 Two copies of chromosome from one parent; none from other
 May or may not cause disease

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 Epigenetics
 Changes in gene function without change in
DNA
 Regulates which genes get turned on and off
 Chemical exposures, diet, endocrine disruptors,
maternal age

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Genetic Implications for Pediatric Care
 Assessment
 Family health history
 Recognition of genetic red flags
 Complete head-to-toe physical/developmental
assessment
 Comprehensive family health history

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 Family Health History and Pedigree
 Three-generation pedigree
 Visual record of genetic links/health-related
information
 Strength/pattern of genetic traits or diseases may
become apparent with this tool
 Insights about families, who share genes and
environments, behaviors, culture
 Include health status of first-, second-, and third-
degree relatives across three generations

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 Family Health History and Pedigree
 Three-generation pedigree

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 Family Health History and Pedigree
 Genetic red flags from history
 Indicate potential for genetic risk
 Rule of Too/Two
• Too many of something
• Two people/events occur
 Multiple affected members with same disorder
 Earlier age at onset than expected for disorder
 Condition/disorder in less-often affected sex
 Appearance of disease in absence of known risk factors
 Ethnicity or ancestral background
 Unusual close relationships – consanguinity
 Multifocal/bilateral occurrence in paired organs
 Intellectual impairment
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 Family Health History and Pedigree
 Physical findings indicating genetic disorders
 Physical abnormalities
• Café au lait spots
• Growth problems
• Congenital anomalies
 Neurological abnormalities
• Hearing/vision loss
• Developmental delay
• Mental retardation
• Seizure disorders

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 Family Health History and Pedigree
 Physical findings indicating genetic disorders
 Minor and major abnormalities
• Genetic etiology considered when one major or more than two
minor abnormalities
 Malformations – birth defects from intrinsic process
 Deformities/disruptions – defects from external process
 Dysplasia – abnormal cellular organization within
tissues resulting in structural change
 Syndrome – set, recurrent pattern of features
 Association – group of anomalies occurring more
frequently than by chance alone

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 Diagnostic Studies
 Screening
 Used in asymptomatic populations to identify those
needing further evaluation
 Newborn screening
 Identifies disorders benefiting from early diagnosis
and treatment
 National Recommended Universal Screening Panel
(RUSP) – 31 core/26 secondary conditions for
screening

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 Diagnostic Studies
 Prenatal screening
 To detect genetic/congenital disorders before birth
• Chorionic villus sample
• Amniocentesis
 Diagnostic genetic testing
 Used to confirm diagnosis
 Main types: karyotype, FISH, biochemical testing,
chromosomal microarray, molecular testing, next
generation sequencing

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 Diagnostic Studies
 Karyotype – identify/evaluate size, shape, number of
chromosomes
 FISH – locate/detect specific area of particular
chromosome
 Biochemical testing – study amount, activity level,
structure of proteins/enzymes
 Chromosomal microarray – to detect micro-deletions or
duplications
 Molecular testing – to detect specific single gene
mutations
 Next-generations sequencing – to detect a single
mutation among many genes
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 Diagnostic Studies
 Carrier testing
 Identifies individuals who have one copy of a gene
mutation
 Usually used for family planning
 Other testing
 Predictive/pre-symptomatic tests for asymptomatic
individuals
 Pharmacological – to learn which dose/drug is best
for individual
 Forensic testing – to establish biological relationships

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 Primary Care Management of
Children with Genetic Disorders
 Genetics referral
 When family history positive
 Children with developmental, growth, and/or structural
disorders
 Genetics counseling a specific aspect of referral

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 Primary Care Management of
Children with Genetic Disorders
 Primary care for children with genetic disorders
 Medical home
 Age-appropriate health supervision guidelines
 Specific guidelines for children with certain conditions

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 Ethical Issues
 Rights to know/not know
 Duty to warn
 Disclosure of incidental findings
 Genetic Information Nondiscrimination Act
(GINA) – to protect individuals from misuse of
genetic information

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 Discussion Questions
1. Access to genomic information is changing the way we practice health care. Today, children and
their parents have the potential to learn about DNA sequence alterations that: (1) confirm
conditions pre-symptomatically (before symptoms appear), (2) predispose children to common
disorders, such as cancer and diabetes, or (3) identify carrier states.
Think about the positive and negative consequences of parents and/or children having access to
this type of information before a child turns 18?
While parents see themselves as gatekeepers of their children’s genetic information (Driessnack
et al, 2013), how do primary care providers balance respect for the parental gatekeeper role and
at the same time advocate for and protect children’s autonomy?
2. Imagine you are conducting a school physical on a 10-year-old child with a history of “anxiety
attacks” with tachycardia. On examination you notice wrist hypermobility, skin elasticity, and
peculiar “cigarette-paper” scars. His mother has been on the Internet and thinks her child may
have either Marfan syndrome or Ehlers-Danlos syndrome. She asks your opinion.
As a primary health care provider, what resources will you turn to? (See Additional Resources)
What further questions/physical findings might you pursue?
Locate referral agencies in your area who you can partner with to diagnose and care for the child
and her/his family.
Anticipate and identify genetic/laboratory tests that could be ordered as part of the child’s
workup.

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